Presbycusis, or age-related hearing loss, is a highly prevalent sensory neurodegenerative condition affecting the majority of our elderly population. Herein we identify several candidate genetic loci which predispose an individual to develop presbycusis. We propose to genotype single nucleotide polymorphisms (SNPs) in these regions and test for associations with measures of hearing ability in our sample of aged human subjects. One advantage of this study is our subject population, one of the best-characterized datasets of its size; accurate phenotyping is critical to the success of any genetic analysis of complex disease. We already have extensive quantitative data and DMA from 610 subjects (535 over age 58), with continuing recruitment of [unreadable] -200 per year. Our first target for investigation is the connexin gene family, implicated in the majority of [unreadable] congenital hearing impairment cases. We hypothesize the same proteins are involved in the similar but less severe phenotype of presbycusis. Our second group of genes has been identified by gene array studies using a mouse model of presbycusis. Our third target is the human leukocyte antigen (HLA) region, which may play a role in the mechanisms of aging, and particularly age-related hearing loss. Our final target is the mitochondrial genome. Inheritance studies indicate a strong genetic component for presbycusis, especially in the maternal lineage, and mitochondrial (mt) DMA is maternally inherited. A gene-environment interaction of a mtSNP with aminoglycoside antibiotics that leads to hearing loss has been well documented. The mt genome has been generally implicated in diseases of aging, but as yet no susceptibility alleles have been identified. A careful study of these four classes of genes should lead to the discovery of some of the molecular bases of susceptibility to presbycusis, which will be important for developing treatments for this common problem of aging. The P.I. already has a strong background in complex trait genetics. In addition to the research goals outlined above, the aim of this proposal is to allow her to gain additional insights into the phenotype under the mentorship of an expert in the field of age-related hearing loss and an expert in statistical genetics. She will attend regular seminars, journal clubs, strategic sessions and annual international meetings on the topics of hearing and aging and will take courses in audition, statistical genetics and the responsible conduct of research. [unreadable] [unreadable] [unreadable]